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Efficacy and Safety Profile of Once-Weekly Dulaglutide in Type 2 Diabetes: a Report on the Emerging New Data

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Efficacy and Safety Profile of Once-Weekly Dulaglutide in Type 2 Diabetes: a Report on the Emerging New Data Journal name: Diabetes, Metabolic Syndrome and Obesity: Targets and Therapy Article Designation: REVIEW Year: 2018 Volume: 11 Diabetes, Metabolic Syndrome and Obesity: Targets and Therapy Dovepress Running head verso: Kugler and Thiman Running head recto: Update on once-weekly dulaglutide in type 2 diabetes mellitus open access to scientific and medical research DOI: http://dx.doi.org/10.2147/DMSO.S134960 Open Access Full Text Article REVIEW Efficacy and safety profile of once-weekly dulaglutide in type 2 diabetes: a report on the emerging new data Anne J Kugler1 Abstract: Dulaglutide is a once-weekly glucagon-like peptide-1 receptor agonist, which has Michael L Thiman2 been on the market in the USA since 2014. Dulaglutide has performed well in head-to-head studies against metformin, glargine, and sitagliptin, where its A1c lowering ranged from 1Department of Pharmacy Practice and Administration, Western -0.78% to –1.64% over 52–104 weeks, and it consistently outperformed each of these agents. University of Health Sciences As an add-on therapy, dulaglutide provided additional A1c lowering of –1.4% to –1.44% College of Pharmacy, Pomona, CA, over monotherapy with glimepiride or glargine at 24 and 28 weeks, respectively. Dulaglutide USA; 2Department of Clinical and Administrative Pharmacy, University outperformed exenatide when added to a regimen of metformin with pioglitazone as well as of Georgia College of Pharmacy, glargine when added to a regimen of metformin with glimepiride. Dulaglutide was shown to Athens, GA, USA be non-inferior to liraglutide when added to metformin. In all AWARD studies other than when For personal use only. compared to liraglutide, dulaglutide at full strength resulted in significantly more patients achieving their A1c goal. Recent class-wide meta-analyses indicate that the incidence of commonly experienced gastrointestinal (GI) side effects is dose dependent, and nausea and vomiting are less common in longer-acting agents such as dulaglutide, but diarrhea may be more common. Pooled data have shown no increased risk of serious side effects such as pan- creatitis or neoplasm with the use of dulaglutide. Given the evidence supporting liraglutide’s cardiovascular benefits, the highly anticipated REWIND trial will have a significant impact on the future place in the therapy of dulaglutide. Keywords: GLP-1 RA, glucagon-like peptide-1 receptor agonist, antidiabetic drugs, diabetes mellitus, injectable, incretin Introduction Glucagon-like peptide-1 (GLP-1) agonists act at GLP-1 receptors in pancreatic beta cells to increase intracellular cyclic AMP, which in turn increases glucose-dependent insulin secretion; in addition, they act to decrease glucagon release and slow gastric ® Diabetes, Metabolic Syndrome and Obesity: Targets Therapy downloaded from https://www.dovepress.com/ by 54.70.40.11 on 29-Dec-2018 emptying. Dulaglutide (Trulicity ; Eli Lilly and Company, Indianapolis, IN, USA) is a long-acting GLP-1 agonist that originally received US Food and Drug Administra- tion (FDA) approval in 2014. The longer half-life of dulaglutide compared to earlier GLP-1 agonists is attributable to alterations that decrease DPP-IV hydrolysis as well as linkage to a constant fragment (F ) that increases protein size and decreases renal Correspondence: Anne J Kugler c 1 Department of Pharmacy Practice and clearance. Administration, Western University of Extensive Phase III study data have been published with regard to dulaglutide, much Health Sciences College of Pharmacy, 309 Second Street, Pomona, CA 91766-1854, of which was part of the AWARD studies, which provide evidence for its use in com- USA bination with several other antidiabetic agents as well as direct comparisons to several Tel +1 909 469 8637 Fax +1 909 469 5539 antidiabetic drug classes. Previously published review articles have provided in-depth Email [email protected] examinations of the earlier AWARD trials.2–5 Since the approval of dulaglutide, several submit your manuscript | www.dovepress.com Diabetes, Metabolic Syndrome and Obesity: Targets and Therapy 2018:11 187–197 187 Dovepress © 2018 Kugler and Thiman. This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms. php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License (http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work http://dx.doi.org/10.2147/DMSO.S134960 you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms (https://www.dovepress.com/terms.php). Powered by TCPDF (www.tcpdf.org) 1 / 1 Kugler and Thiman Dovepress follow-up Phase III and Phase IV data have been published Top Injection button providing additional insights into clinical use of this agent. Lock ring The purpose of this article is to review emerging clinical data Indicator pertaining to the efficacy and safety of dulaglutide in type 2 Lock/unlock diabetes mellitus (T2DM). Literature search strategy A nonsystematic search was conducted on PubMed, Embase, and Cochrane Library using the following search terms: dulaglutide, LY2189265, Trulicity, glucagon-like peptide-1 Medicine receptor agonists (RAs), or GLP-1 RA. The limits imposed Clear base were English language, human studies, and original research, Bottom/ without any limitation of date range. Articles were filtered needle manually to remove duplicate studies, conference abstracts, end Base cap and studies in patients without T2DM. To ensure complete- Figure 1 Dulaglutide injection device. Note: Reproduced with permission Trulicity (dulaglutide) injection, solution ness, bibliographies of relevant review articles and meta- [instructions for use] Indianapolis, IN: Eli Lilly and Company; 2016. Copyright ©2016 47 analyses were also reviewed. Eli Lilly and Company. All Rights Reserved. Pharmacokinetics Review of Phase III trial data The maximum plasma concentration of dulaglutide is Within the AWARD study sequence, two trials compared achieved at a median of 48 hours following subcutane- dulaglutide to oral antidiabetic agents, specifically metfor- ous administration, but a period of 2–4 weeks of weekly min (AWARD-3) and sitagliptin (AWARD-5). AWARD-3 For personal use only. medication administration is needed to achieve steady state, was a 52-week study that randomized patients to dulaglutide which is not significantly impacted by the location of injec- (0.75 mg weekly), dulaglutide (1.5 mg weekly), or metformin tion. Dulaglutide is broken down into its component amino (twice daily). Enrolled patients included those with baseline acids by general protein catabolism pathways and is not A1c values of ≥6.5% and ≤9.5% with only lifestyle manage- impacted by the CYP450 isoenzymes or P-glycoprotein. ment or a single, low-dose oral antidiabetic agent. Previous The primary drug interactions of note involve concur- antidiabetic therapy was discontinued during the study lead-in rent use of antidiabetic medications such as insulin or period. Dulaglutide (1.5 mg) demonstrated a significantly sulfonylureas and increased risk of hypoglycemia. Elimi- greater A1c reduction from a baseline of 7.6% compared to nation half-life for both the 0.75 and 1.5 mg weekly doses metformin at 52 weeks, with a significantly greater proportion is about 5 days. No dose adjustment is required for age, of patients achieving A1c values of less than both 6.5% and gender, race, ethnicity, body weight, or renal or hepatic 7% at the study end. No difference in serious adverse events impairment.6 (AEs) was noted, and only constipation was found to occur at a higher rate in the dulaglutide treatment groups compared to Mode of administration metformin. Weight loss was comparable between dulaglutide It is recommended to inject dulaglutide subcutaneously in (1.5 mg) and metformin.8 Details of efficacy parameters in Diabetes, Metabolic Syndrome and Obesity: Targets Therapy downloaded from https://www.dovepress.com/ by 54.70.40.11 on 29-Dec-2018 the abdomen, thigh, or upper arm and to rotate the injection AWARD trials are summarized in Table 1, and select safety site. It is available as a single-dose pen containing 0.5 mL end points are detailed in Table 2. AWARD-5 was a 104-week of solution, containing 0.75 or 1.5 mg of active drug and study that randomized patients receiving metformin to either equipped with a locking mechanism to prevent unintentional dulaglutide (0.75 mg weekly), dulaglutide (1.5 mg weekly), or injection (Figure 1). No additional pen needle prescription is sitagliptin (100 mg daily). Patients were eligible for enrollment required, as a needle is already a part of the single-use device. if they were managed with lifestyle modification only and had No shaking or mixing is required, but the solution should be baseline A1c values of >8% and ≤9.5% or were managed on visually inspected for particulate matter and discoloration two or fewer oral antidiabetic agents with baseline A1c values prior to administration.6 A medication guide is required to of ≥7% and ≤9.5%. At study conclusion, both doses of dula- be dispensed with dulaglutide.7 glutide demonstrated significant A1c reduction from baseline 188 submit your manuscript | www.dovepress.com Diabetes, Metabolic Syndrome and Obesity: Targets and Therapy 2018:11 Dovepress Powered by TCPDF (www.tcpdf.org)
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